Initial studies have shown that the pregnant mouse is deficient in its ability to form antibodies to the T-dependent antigen, sheep red blood cells (SRBC). Suppression, compared with nonpregnant controls, was greatest for gamma A plaques, less for gamma G and least for gamma M. Pregnant, fetal and newborn mouse sera were found to inhibit antibody synthesis in vitro. We plan to extend these studies to larger number of animals and to determine the chemical nature of suppressive factor(s) in pregnant and newborn serum. Recent work from our laboratory has shown that alpha-fetoprotein (AFP) is a potent immunosuppressor and, therefore, this protein could be one important factor. Affinity chromatography employing a monospecific anti-AFP will be used to determine whether removal of AFP from sera affects their suppressive properties. Synthesis of AFP will be studied in tissues of the fetal and pregnant animals, including the liver, spleen, intestinal tract, thymus, and in the trophoblast of the placenta, in an attempt to determine whether the elevated levels of AFP in pregnant sera result from transport from the fetus or maternal synthesis or both. Both the fluorescent antibody and in vitro culture systems involving incorporation of C14 amino acids into AFP will be employed. Levels of AFP in the mother and the fetus will be measured during gestation using a double antibody radioimmunoassay. We will attempt, using the fluorescent antibody technique, to detect AFP on the surface of lymphocytes at various stages during pregnancy. The homing of lymphoid cells derived from the gut (Peyer's patches and lamina propria) will be studied in order to determine whether the striking deficiency in gamma A antibody response in pregnant animals results from a movement of gamma A cells into the mammary tissues during later pregnancy. The effect of AFP on the dosage required to produce tolerance in adult animals will be investigated using human gamma globulin as an antigen. If tolerance is affected by AFP, other antigens will be tested and experiments outlined to determining whether T or B cells are tolerized. Finally, the possibility of suppressor cells being responsible for the immune deficiencies noted in pregnant and neonatal animals will be explored both in vitro and in vivo, the latter by the transfer of cells from pregnant and newborn animals into syngeneic recipients.